Generalized resistance of thyroid hormone (GRTH) is an inherited disease linked to mutations in the beta T3 receptor gene and characterized clinically by the resistance of peripheral and pituitary tissues to the action of thyroid hormone. Of the over 30 different mutations identified in the ligand binding domain of the beta receptor, several were shown to inhibit normal receptor function by a dominant negative mechanism which is likely to mediate the phenotype of this disease. Recent studies have indicated that this dominant negative effect is most likely mediated by competition of mutant and normal receptor for binding to T3 response elements within various thyroid hormone responsive genes. We have recently shown that natural thyroid hormone response elements (TRE's) show variation in the dominant negative effect compared to previously employed artificial TRE's. Both normal and several mutant receptors have been cloned into a vector which is expressed in a baculovirus/insect cell system. Such eukaryotic receptors are being characterized with respect to phosphorylation, DNA and ligand binding, transcriptional capability and structure. We have also continued detailed clinical studies of 38 unrelated kindreds comprised of approximately 100 affected individuals and 100 unaffected siblings used as controls.